Our long-term objective is to unravel the molecular genetics of hereditary human blinding diseases, such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD). Genetic defects that lead to photoreceptor cell death in AMD and RP are highly heterogeneous and now include a list of more than 132 genes. The complex and various clinical and genetic findings in AMD and RP suggest that there are multiple subtypes of the diseases, each with a distinct genetic and biochemical basis. This complexity, the infrequent availability of ocular tissues from RP and AMD patients, and the broad base of knowledge of Drosophila genetics, all combine to make Drosophila a powerful animal model for studying inherited retinal degeneration disorders. We propose to use Drosophila as a model to identify and characterize novel loci in human blinding diseases, providing mechanistic insights into the molecular basis of retinal degeneration. We will use an integrated strategy of genetic, biochemical, cell biological, electrophysiological, and molecular approaches to uncover the diverse molecular signaling mechanisms that coordinate protein biosynthesis in photoreceptor cells. Our research focuses on those events that ensure correct folding, modification, oligomeric assembly, quality control, trafficking and targeting of newly synthesized proteins. Defects in these processes often stimulate extensive cellular responses that lead to pathogenesis and, in severe cases, neurodegeneration. Here, we will characterize the molecular chaperone calnexin, and 4 novel loci that function in the calnexin pathway: cip1, cip2, cip3 and cip4. Calnexin is a molecular chaperone that promotes the proper folding of nascent glycoproteins in the endoplasmic reticulum (ER). Upon exiting the ER, newly folded proteins must be transported to the Golgi where they undergo a new set of modifications. Transport of proteins between the two compartments occurs via the budding and fusion of vesicles. We will characterize a novel photoreceptor SNARE protein required for vesicular fusion events in the Golgi. We have shown that mutations in calnexin, cip1-4 and the snare gene cause defects in rhodopsin expression and lead to retinal degeneration. Our findings will be used to screen human AMD and RP pedigrees for similar mutations. We aim to uncover novel loci in blinding diseases, provide insights into the molecular mechanisms of retinal degeneration, and offer therapeutic approaches for treating RP and AMD.